Effects of Dietary Sodium and Magnesium on Cyclosporin A–Induced Hypertension and Nephrotoxicity in Spontaneously Hypertensive Rats

Mervaala, Eero; Père, A; Lindgren, L.; Laakso, Juha; Teräväinen, Terttu-Liisa; Karjala, Kirsi; Vapaatalo, Heikki; Ahonen, J; Karppanen, Heikki

doi:10.1161/01.hyp.29.3.822

Cited by 50 publications

(35 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…21 In SHR, this exact CsA regimen produces a final tissue concentration of CsA in the heart that is almost 4 times higher than in the skeletal muscle. 20 Our results differ from those of Sussman et al 11 who reported that systemic CsA virtually eliminated LVH not only in several transgenic mouse models of sarcomeric disruption but also in rats with aortic banding. Whereas the study of Sussman et al 11 focused mainly on transgenic mouse models of dilated cardiomyopathy, our study provides a more comprehensive examination of pressure-overload hypertrophy in rats.…”

Section: Discussioncontrasting

confidence: 99%

“…The age of 5 weeks was chosen because this predates the onset of hypertension and LVH in SHR. 19,20 At the 6-week end point, rats were anesthetized with methohexital sodium (Eli Lilly; 50 mg/kg IP). A catheter was inserted into the left carotid artery and tunneled subcutaneously to exit from the nape for subsequent measurements of arterial pressure in the conscious state.…”

Section: Protocol 1: Effects Of Csa On Lvh In Shrmentioning

confidence: 99%

“…In SHR, CsA (5 mg/kg), as expected, was sufficient to raise blood pressure by 14Ϯ5 mm Hg (PϽ0.05 versus vehicle), but it had no effect on the development of LVH, as measured by left ventricular weight to body weight (LVW/BW) ratios (Table 1). Five milligrams per kilogram was chosen because this systemic dose of CsA is clinically relevant, produces high concentrations of CsA in blood and heart, 20 and was shown to effectively inhibit calcineurin-mediated signaling in skeletal muscle of SHR. 21 …”

Section: Effects Of Csa In Shrmentioning

confidence: 99%

See 2 more Smart Citations

Failure of Calcineurin Inhibitors to Prevent Pressure-Overload Left Ventricular Hypertrophy in Rats

Zhang

Kowal

Rusnak

et al. 1999

Circulation Research

127

View full text Add to dashboard Cite

Abstract-A rapidly emerging body of literature implicates a pivotal role for the Ca 2ϩ -calmodulin-dependent phosphatase calcineurin as a cellular target for a variety of Ca 2ϩ -dependent signaling pathways culminating in left ventricular hypertrophy (LVH). Most of the recent experimental support for this hypothesis is derived from in vitro studies or in vivo studies in transgenic mice expressing activated calcineurin or mutant sarcomeric proteins. The aim of the present study was to test whether calcineurin inhibitors, cyclosporin A (CsA) and FK 506, prevent pressure-overload LVH using 2 standard rat models: (1) the spontaneously hypertensive rat (SHR) and (2) aortic banding. The major new findings are 2-fold. First, in SHR, LVH (left ventricular weight to body weight ratio) was unaffected by a dose of CsA (5 mg ⅐ kg Ϫ1 ⅐ d Ϫ1) that was sufficient to raise blood pressure and to inhibit calcineurin-mediated transcriptional activation in skeletal muscle. Second, in rats with aortic banding, LVH was unaffected by FK 506 (0.3 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ) or even higher doses of CsA (10 and 20 mg ⅐ kg) that were sufficient to inhibit 90% of total calcineurin phosphatase activity in the hypertrophied myocardium. In the latter experiments, CsA blocked neither the elevated left ventricular end-diastolic pressures, a measure of diastolic function, nor the induction in atrial natriuretic peptide mRNA in the hypertrophic ventricles. Thus, in numerous experiments, systemic administration of potent calcineurin inhibitors did not prevent the development of LVH in 2 classic models of pressure-overload hypertrophy. These results demonstrate that pressureoverload hypertrophy can arise through calcineurin-independent pathways. (Circ Res. 1999;84:722-728.) Key Words: left ventricular hypertrophy Ⅲ calcineurin Ⅲ cyclosporin A Ⅲ spontaneously hypertensive rat Ⅲ aortic banding I n patients with many forms of heart disease, the development of left ventricular hypertrophy (LVH) constitutes one of the most powerful predictors of subsequent cardiovascular morbidity and mortality. 1-3 Increased left ventricular mass strongly predicts an increased incidence of cardiovascular death, myocardial infarction, angina requiring revascularization, stroke, and congestive heart failure. Despite the clinical importance of LVH, the underlying mechanisms mediating the hypertrophic process have been enigmatic.A variety of intrinsic and extrinsic pathological stimuli can initiate a hypertrophic response in the left ventricle. Extrinsic stimuli include pressure overload, volume overload, and neurohumoral factors. Intrinsic stimuli include contractile abnormalities resulting from altered expression or mutations of sarcomeric proteins. Although these diverse stimuli are known to activate diverse intracellular signal transduction pathways, 4 it is unknown whether these various pathways ultimately converge on a final common signaling pathway culminating in cardiomyocyte hypertrophy. 4 -6 In this regard, changes in [Ca 2ϩ ] i have been proposed to play a pivotal rol...

show abstract

Section: Discussioncontrasting

confidence: 99%

Section: Protocol 1: Effects Of Csa On Lvh In Shrmentioning

confidence: 99%

Section: Effects Of Csa In Shrmentioning

confidence: 99%

See 1 more Smart Citation

Failure of Calcineurin Inhibitors to Prevent Pressure-Overload Left Ventricular Hypertrophy in Rats

Zhang

Kowal

Rusnak

et al. 1999

Circulation Research

127

View full text Add to dashboard Cite

show abstract

“…Mounting evidence from animal, epidemiological, and clinical studies suggests that a high dietary salt intake is associated with myocardial hypertrophy. [2][3][4][5][6] Although the mechanism of salt-induced myocardial hypertrophy is poorly understood, dietary salt intake is thought to modify the process of myocardial hypertrophy by hemodynamic and/or nonhemodynamic mechanisms. 7 The development of cardiac hypertrophy in response to pressure and/or volume overload is generally considered to be an adaptive mechanism to normalize ventricular wall stress.…”

mentioning

confidence: 99%

Sodium Induces Hypertrophy of Cultured Myocardial Myoblasts and Vascular Smooth Muscle Cells

et al. 1998

View full text Add to dashboard Cite

Abstract-The mechanisms of sodium-induced myocardial hypertrophy and vascular hypertrophy are poorly understood.We tested the hypothesis that a high sodium concentration can directly induce cellular hypertrophy. Neonatal rat myocardial myoblasts (MMbs) and vascular smooth muscle cells (VSMCs) were cultured in a 50:50 mixture of DMEM and M199 supplemented with 10% fetal bovine serum. Key Words: sodium Ⅲ hypertrophy Ⅲ myocardial myoblasts Ⅲ muscle, smooth, vascular S odium homeostasis profoundly influences the cardiovascular system in normotensive and hypertensive subjects and is a major risk factor for cardiovascular morbidity and mortality independent of other cardiovascular risk factors (for review, see Reference 1). Mounting evidence from animal, epidemiological, and clinical studies suggests that a high dietary salt intake is associated with myocardial hypertrophy. [2][3][4][5][6] Although the mechanism of salt-induced myocardial hypertrophy is poorly understood, dietary salt intake is thought to modify the process of myocardial hypertrophy by hemodynamic and/or nonhemodynamic mechanisms. 7The development of cardiac hypertrophy in response to pressure and/or volume overload is generally considered to be an adaptive mechanism to normalize ventricular wall stress. High blood pressure is one of the most powerful determinants of LVH, 8 and several studies 5,9 -11 have shown that a high dietary salt intake is associated with increased blood pressure. Therefore, many investigators consider an increased pressure load on the myocardium to be a major cause of LVH in subjects with salt-induced hypertension.More recent evidence points to a close relationship between the development and persistence of LVH and sodium intake, which may be independent of blood pressure. 2,4,6,[12][13][14] Frohlich and associates 12 reported that a high sodium diet not only caused further cardiac enlargement in spontaneously hypertensive rats but also increased cardiac mass in normotensive Wistar-Kyoto rats in the absence of increased blood pressure. Studies in humans have shown that the intracellular sodium concentration of red blood cells is positively correlated with the degree of LVH. 15 Together these results suggest that sodium-induced cardiac hypertrophy may be partially mediated by a direct action of sodium on the myocardium, independent of hemodynamic factors.The present study sought to determine whether sodium can directly induce hypertrophy of individual cells that are not exposed to many of the in vivo factors, such as high blood pressure or increased cardiac output, commonly associated with a high salt diet. The results indicate that increasing the concentration of sodium in cell culture medium can induce hypertrophy of neonatal rat MMbs and VSMCs. The hypertrophy

show abstract

“…Animal studies [27][28][29] have concluded that a low sodium intake may amplify the nephrotoxic effect of cyclosporine. However, these studies examined the effect of sodium depletion rather than a moderate sodium restriction and cannot be applied to human low sodium diets.…”

Section: Adverse Effects Of Restricted Sodium Intakementioning

confidence: 99%

Nutritional management of hypertension in adult kidney transplant recipients

Chadban¹,

Chan²,

Fry³

et al. 2010

Nephrology

View full text Add to dashboard Cite

GUIDELINESNo recommendations possible based on Level I or II evidence. SUGGESTIONS FOR CLINICAL CARE(Suggestions are based on Level III and IV evidence).• Stable hypertensive kidney transplant recipients should be advised to restrict sodium intake to 80-100 mmol/day. (Level III evidence)• Based on studies in the general population kidney transplant recipients should:-When overweight or obese, be encouraged and supported to reduce their weight. (Refer to CARI Guideline: Nutritional management of overweight and obesity in adult kidney transplant patients).-Be encouraged to do at least 30 min of moderate intensity physical activity on at least 5 days per week.• Alcohol should be limited to no more than two standard drinks on any day for both men and women. This advice is based on NHMRC guidelines for lifetime health risks associated with daily alcohol consumption by 'healthy' men and women. 1 • Lowering sodium intake to 65-70 mmol per day may cause a greater lowering of blood pressure. BACKGROUNDThe development of arterial hypertension is common after kidney transplantation. While the aetiological factors of post-transplant hypertension have not been clearly elucidated, it has been correlated with male sex, age, donor age, the presence of diabetes, weight gain, body mass index and delayed graft function.2 Calcineurin inhibitors are known to contribute to hypertension and prednisone may also play a role. 3,4 Post-transplant arterial hypertension is a risk factor for cardiovascular disease (CVD), which is a significant cause of morbidity and mortality in the kidney transplant population.5 Hypertension appears to be one of the primary risk factors for carotid lesions in the kidney transplant recipients, with such lesions being associated with a five-to sixfold increase in myocardial infarction or stroke in the general population. 6In the non-transplant population, the relationship between blood pressure and risk of CVD events is continuous, consistent and independent of other risk factors. For each 20 mmHg rise in systolic blood pressure or 10 mmHg rise in diastolic blood pressure above 115/75 mmHg, the risk of CVD is doubled (in people aged 40-70 years).7 Conversely, a reduction of 5 mmHg diastolic blood pressure is associated with a 35-45% fall in risk of stroke.8 Treating hypertension successfully may significantly affect the progression of CVD in the transplant population in a similar manner.Recent studies have shown that hypertension is associated with chronic allograft nephropathy and acute rejection. An elevated blood pressure, even within the normal range, has been shown to adversely affect kidney graft survival. 9There is sufficient evidence from observational studies (in addition to the randomized trials in the general population) to support the vigorous treatment of hypertension in kidney transplant recipients.Clinical trials in the general population have shown that lifestyle modifications are fundamental to blood pressure control. Weight reduction, 10,11 increasing physical activity, 12,13 consuming a die...

show abstract

Effects of Dietary Sodium and Magnesium on Cyclosporin A–Induced Hypertension and Nephrotoxicity in Spontaneously Hypertensive Rats

Cited by 50 publications

References 30 publications

Failure of Calcineurin Inhibitors to Prevent Pressure-Overload Left Ventricular Hypertrophy in Rats

Failure of Calcineurin Inhibitors to Prevent Pressure-Overload Left Ventricular Hypertrophy in Rats

Sodium Induces Hypertrophy of Cultured Myocardial Myoblasts and Vascular Smooth Muscle Cells

Nutritional management of hypertension in adult kidney transplant recipients

Contact Info

Product

Resources

About